Inflammatory complications in CVID-

what is new and what can be done?

Peter Bergman, MD, PhD Assoc Prof, Consultant Physician

Dept of Laboratory Medicine, Clinical Microbiology

Karolinska Institutet

Immunodeficiency Unit,

Karolinska University Hospital, Stockholm, Sweden

Infektionsveckan och Mikrobiologiskt Vårmöte 2019

PID-patient care: an area in rapid transition

19/05/2019 Name Surname 2

What is a PID-patient?

19/05/2019 4

PID-patients

Infectious diseases

Microbiology Immunology

Clinical genetics

Neurology

Diagnosis and clinical work-up

Case: Robert, 35 years

Normal childhood, bi-linear Evan’s syndrome diagnosed at age

17 (Tpk, RBC), increased susceptibility to infections around age

25, referred from hematology to us at age 31

IgG: 2.2 g/L, IgA: 0, IgM: 0

No vaccine response, low memory B-cells, splenomegaly,

Evan’s syndrome

CVID diagnosis was given and scIG was started

Few infections, occasional findings of H. Influenzae in sputum

Last 6 months: Gradual deterioration of general appearence

Very tired, nightly chills, bad physical performance

Difficult to work and to take care of his family with a newborn

baby 19/05/2019 Inflammation in CVID 5

Main problem for Robert: the lungs

Spirometry: Static lungvolumes: 63% of expected; Dynamic

spirometry: 60%, Diff capacity: 74%

Pulmonary X-ray: ”diffuse infiltrations bilaterally of unspecific

nature”.

PET-CT: ”several multiple hyper-metabolic nodules in the gut,

along the aorta, inguinal, axillar, spleen and in the lung”

BAL: no malignant cells, no TB, fungi, virus or bacteria,

hyperinflammatory and mixed cellular pool

Needle punction of a lung infiltrate: mixed lymfocytic infiltration,

no malignant cells, no granuloma

How should this patient be handled?

19/05/2019 Inflammation in CVID 6

How is CVID defined?

Main criteria:

Clinical symptoms: infections, autoimmunity or

lymphoproliferation (at least one)

Hypogammaglobulinemia (at least 2 measurements, 3 weeks

apart)

Low IgA or IgM

Low or absent response to polysaccarides or protein antigens

Other causes to hypogammaglobulinemia should be excluded

Supporting: reduced memory B cell subsets and/or increased

CD21-low subsets by flow cytometry

19/05/2019 Inflammation in CVID 7

ESID Criteria 2015

Common Variable Immunodeficiency

Facts about CVID

Unknown cause

Prevalence is around 1:20.000-1:30.000

Onset can occur in children or adults

Usually long time from onset of symptoms to diagnosis

Not directly inherited, i.e not mendelian genetics

A Danish study (2017)

Prevalence 1:26.000

Median age onset of symptoms = 29 years

Median age at diagnosis = 40 years

Median diagnostic delay = 7 years

19/05/2019 Inflammation in CVID 8

Westh et al, 2017

19/05/2019 9

Jolles et al, 2013

Lymphocytic Interstitial Pneumonia

Lung

Intestine

Liver

S. pneumoniae

H. influenzae

S. aureus

M. catarrhalis

P. aeruginosa in BE

Giardia

Salmonella

C. jejuni

Norovirus

Ureaplasma

Mycoplasma

Clinical phenotypes in CVID

19/05/2019 Inflammation in CVID 10

Jolles et al, 2013

Intestinal problems in CVID

GI symptoms in 103 CVID-patients and GI histopathological findings in 53 CVID-patients

Symptoms: bloating (34%), pain (30%), and diarrhea (26%).

Histopathology:

increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., “celiac-like

disease” (46% of patients),

decreased numbers of plasma cells in GI tract mucosa (62%)

lymphoid hyperplasia (38%),

Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics

of CVID, and increased serum levels of sCD14 ( P =0.025), sCD25 ( P =0.01), and sCD163

(P =0.04).

Norovirus infection was not found as a cause of CVID enteropathy (none)

19/05/2019 Inflammation in CVID 11

Jorgensen et al, 2016

A recent study where this question was addressed:

Almost 50% of CVID-patients had inflammation as shown with PAD

Around 30% had GI-symptoms

19/05/2019 Inflammation in CVID 12

Jorgensen et al, 2016

CVID

Normal

Small intestine

(lymphocytic infiltrates)

Colon

(fewer plasma-cells)

Small intestine

(lymphoid aggregates)

Intestinal problems are common in CVID

Medical history

Monitoring with fecal calprotectin

Gastroscopy

Colonoscopy

Discussion with gastroenterologists

19/05/2019 Name Surname 13

Liver disease in CVID

19/05/2019 Inflammation in CVID 14

Song et al, 2017

Liver disease in CVID can occur – but is less

common than GI-problems

We follow our patients with liver enzymes, GT, ALP

Regular ultrasound to monitor potential hepatomegaly /

splenomegaly

If pathological findings – discussion with hepatologists

19/05/2019 Name Surname 15

Lung disease in CVID: Bronchiectasis

10-20 % of CVID-patients

Likely a consequence of frequent infections

A marker for lung-damage

Could lead to chronic colonisation by opportunistic bacteria

19/05/2019 Inflammation in CVID 16

Bronchiectasis is not associated with other

CVID-related co-morbidities

19/05/2019 Inflammation in CVID 17

Gathmann et al, 2014 N=2212 patients from the ESID-registry

GLILD: granulomatous lymphocytic

interstitial lung disease

Clinical: dyspnea, fatigue, low-grade fever

Physiology: static, dynamic and diff cap

Radiology: HRCT, ground-glass appearance, nodules

Nuclear medicine: PET/CT, hypermetabolic nodules

Fibroscopy, BAL: inflammatory cells only, no malignant cells, no

infection

PAD, Histology: lymphocytic infiltrations, nodular aggregates

Other causes should be excluded (TB, lymphoma and

sarcoidosis)

19/05/2019 Inflammation in CVID 18

GLILD is sign of immundysregulation

Approximately 10–20 % of patients with CVID develop GLILD

Splenomegaly and adenopathy

Cytopenias and evidence of immune dysregulation, with T cells skewed toward

a memory phenotype

Histologic evaluation of pulmonary and lymphatic tissue is most consistent with

dysregulated lymphoproliferation (T- and B-cells).

GLILD appears to be the pulmonary manifestation of a generalized, multi-

systemic lymphoproliferative disease.

19/05/2019 Inflammation in CVID 19

GLILD requires immunosuppressive therapy

Steroids can work, but not always

Rituximab (weekly doses of IV rituximab (375

mg/m2/infusion) for 4 weeks

Azathioprine (oral, 1.0– 2.0 mg/kg/day, 18 months

duration).

Rituximab infusions were repeated at 4–6 month

intervals, for 3 or 4 total courses (12–16 infusions).

Evaluation together with pulmonologists

No consensus on the optimal protocol or if other

treatments can be better.

19/05/2019 Inflammation in CVID 20

Chase et al, 2013

Before

After

Rituximab and mycophenolate mofetil, 3 months treatment

Improvement measured by PET-CT (FDG-uptake)

Improved lung-function and physical performance

19/05/2019 Inflammation in CVID

21

Jolles et al, 2016

19/05/2019 Inflammation in CVID 22

Jolles et al, 2016

GLILD is connected to a bad prognosis

19/05/2019 Inflammation in CVID 23

Bates et al, 2004

GLILD: how bad is it?

19/05/2019 Inflammation in CVID

24

Odnoletkova et al, 2018

GLILD management: recommendations

19/05/2019 Inflammation in CVID 25

Hurst et al, 2017

First line: corticosteroids 30-70 mg/day

Increase in serum IgM is a marker for

progressive lung disease

Monocytes produce BAFF, which stimulate B-cells to proliferate

and produce IgM

Rituximab reverse this process and improve symptoms

19/05/2019 Name Surname 26 Maglione et al, 2019

What is the mechanism behind GLILD?

What about whole genome sequencing and

CVID?

< 5% genetic causes to CVID-like syndromes

CVID is likely to be a polygenic disease with multiple novel

susceptibility loci implicated (Orange et al, 2011)

Application of whole genome sequencing has revealed several

key genes for CVID

TACI

CD19

CD81

CD21

NFKB

And more

19/05/2019 Name Surname 27

It is likely that CVID will be divided in many different subgroups or separate

diagnostic entities in the future

Ameratunga et al, 2018

Complex genetic network in CVID

TACI

NLRP12

BAFF-R

SKIV2L

19/05/2019 Name Surname 28

Van Schouwenburg et al, 2015

34 CVID-patients

WGS + RNAseq

< 5% of CVID-patients have a known genetic cause to their

disease and >95% do not have a known disease gene

implicated

Back to our patient: what happened?

We decided to start with immunsuppression:

Important to rule out lymphoma (a lymph-node should be

examined)

Check latent HBV (HBsAg, HBV DNA, anti-HBc, can be positive

due to IgG-substitution)

Check latent TB (PPD + IGRA-test)

Rule out Sarcoidosis (ACE, can be high due to inflammation)

Prednisolone (Sarcoidosis-protocol, start 40 mg/day, down to

10-15 mg/day)

New PET-CT after 3 months showed almost complete remission

of hypermetabolic nodules

Clear improvement of general appearence and physical

condition – but for how long?

19/05/2019 Name Surname 29

Final reflections and take home messages

CVID-patients are out there: please find them and refer them!

CVID with inflammatory complications is connected with high

morbidity and mortality.

CVID is most likely several different disorders from a genetic

perspective

We lack information about underlying mechanisms

We lack prognostic markers

PID is definitely more than infections – we need to think

”immunodysregulation”.

Immunosuppression should be used more often in CVID-

patients with inflammation.

Multidisciplinary work is necessary!

19/05/2019 Inflammation in CVID 30

The Team at Karolinska Univ Hospital

Our Doctors:

Dr. Anna-Carin Norlin, MD, PhD

Dr. Peter Bergman, MD, PhD, Assoc Prof.

Dr. Emelie Wahren-Borgström, MD, PhD

Prof Edvard Smith, MD, PhD

Dr. Rolf Gustavsson, MD, PhD

Our nurses:

Susanne Hansen

Kristina Johansson

Maria Lindén

Our aim is to develop a ”National Competence Center” within the area of

Primary Immunodeficiency in adults. Please, contact us for referalls.

19/05/2019 Inflammation in CVID 31

Research network

Petter Brodin

Yenan Bryceson

Kristian Riesbeck

Fredrik Kahn

Thank’s for your attention!

If you have further questions or comments, please contact me at:

peter.bergman@ki.se

19/05/2019 Name Surname 32